Role of heparin binding growth factors in vascular leakage and fatal bleeding

肝素结合生长因子在血管渗漏和致命性出血中的作用

• 批准号: 8963247
• 负责人: PATRICIO E RAY
• 金额: $ 43万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-21 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963247
• 关键词: A Mouse; Affect; Angiopoietin-1; Angiotensin II; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Arteries; Biological Assay; Biological Markers; Blood Circulation; Blood Pressure; Blood Vessels; Capillary Leak Syndrome; Capillary Permeability; Cardiopulmonary Bypass; Child; Clinical; Coagulants; Critically ill children; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP; Data; Development; Disease; Early identification; Early treatment; Endothelial Cells; Equilibrium; Event; Extracorporeal Membrane Oxygenation; Extravasation; Fibroblast Growth Factor 2; Functional disorder; Growth Factor; Hemorrhage; Heparin; Heparin Binding; Heparin Binding Growth Factor; Hypotension; Inflammatory; Intervention; Intestines; Knowledge; Mesentery; Mus; Nitric Oxide; Organ; Outcome; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Plasma; Play; Postoperative Period; Procedures; Process; Regulation; Resistance; Risk; Role; Sampling; Signal Pathway; Signal Transduction; Testing; Urine; Vascular Endothelial Growth Factors; Vascular Permeabilities; base; cytokine; high risk; improved; inhibitor/antagonist; mouse model; novel; prevent; prospective; public health relevance; research study; rho

 DESCRIPTION (provided by applicant): Critically ill children treated with heparin during extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB), are at high risk of developing severe capillary leak syndromes (CLS) and excessive bleeding (EB). These events are attributed to multifactorial causes, including inflammatory cytokines and the anti-coagulant activity of heparin. Very little is known, however, about the role that heparin-binding angiotenic growth factors (HBGFs), acting in synergy with heparin-like drugs, play in this process. A nonsurgical intervention that can effectively control postoperative vascular leakage and bleeding is needed. This proposal is based on our novel observation that Fibroblast Growth Factor-2 (FGF-2), a heparin binding angiogenic growth factor, plays a critical role precipitating lethal bleeding disorders in mice treated with heparin-like drugs. In addition, we found that Angiopoietin-1 (Ang-1), an anti-permeability-anti-inflammatory angiogenic growth factor, can prevent lethal bleeding complications in mice without normalizing their anticoagulant status. Based on these findings, we hypothesize that FGF-2 and other HBGFs, tip the balance to precipitate CLS and EB by inducing changes in vascular tone and permeability in combination with heparin-like drugs. Furthermore, we propose that blocking the permeability signaling pathways induced by heparin + FGF-2 will prevent these complications. Finally, we hypothesize that FGF-2 and other HBGFs will become reliable biomarkers to identify children at high risk of developing CLS and EB. Three aims will be explored. In aim 1, will test the hypothesis that heparin, in synergy with FGF-2, induce vascular leakage and bleeding complications by affecting the vascular activity of Angiotensin II (Ang II), VEGF-A, and nitric oxide (NO). In aim 2 we will identify the basic mechanisms through with Ang-1 prevents the development of severe bleeding complications induced by heparin + FGF-2, and test the hypothesis that blocking the Rho-A, Src, Tek (Tie-2) and other signaling - inflammatory pathways will prevent lethal bleeding complications in mice. In aim 3, we will follow the clinical outcome of children treated with ECMO and CPB, and define the clinical value of FGF-2 and other HBGFs as biomarkers to identify children at risk of developing severe CLS and EB. These experiments will generate new knowledge and treatments to prevent CLS and EB in children treated with ECMO and CPB, and establish the new notion that blocking the early capillary permeability changes induced by heparin + FGF-2 will prevent CLS and EB in these patients without normalizing their anti-coagulant status.

 描述(由申请人提供)：在体外膜氧合(ECMO)和体外循环(CPB)期间使用肝素治疗的危重儿童，有发展为严重毛细血管渗漏综合征(CLS)和大量出血(EB)的高风险。这些事件被归因于多因素的原因，包括炎症细胞因子和肝素的抗凝活性。然而，人们对肝素结合的血管紧张生长因子(HBGFs)与肝素类药物协同作用在这一过程中所起的作用知之甚少。需要一种能有效控制术后血管渗漏和出血的非手术干预措施。这一建议是基于我们新的观察结果，即成纤维细胞生长因子-2(成纤维细胞生长因子-2)，一种与肝素结合的血管生成生长因子，在使用肝素类药物治疗的小鼠中发挥关键作用，导致致命的出血疾病。此外，我们还发现，血管生成素-1(Ang-1)是一种抗渗透-抗炎的血管生成生长因子，可以在不使小鼠的抗凝状态正常化的情况下预防致命的出血并发症。基于这些发现，我们假设成纤维细胞生长因子-2和其他HBGFs通过结合肝素类药物诱导血管张力和通透性的改变来平衡CLS和EB。此外，我们认为阻断肝素+成纤维细胞生长因子-2诱导的通透性信号通路可以预防这些并发症。最后，我们假设成纤维细胞生长因子-2和其他HBGFs将成为识别CLS和EB高危儿童的可靠生物标志物。我们将探讨三个目标。在目标1中，将验证这样的假设，即肝素与成纤维细胞生长因子-2协同作用，通过影响血管紧张素II(Ang II)、血管内皮生长因子-A(VEGF-A)和一氧化氮(NO)的活性而导致血管渗漏和出血并发症。在目标2中，我们将通过Ang-1预防肝素+成纤维细胞生长因子-2诱导的严重出血并发症的基本机制，并验证阻断Rho-A、Src、Tek(Tie-2)等信号-炎症通路将预防小鼠致死性出血并发症的假说。在目标3中，我们将跟踪观察接受ECMO和CPB治疗的儿童的临床结果，并确定成纤维细胞生长因子-2和其他HBGFs作为生物标志物的临床价值，以识别儿童发展为严重CLS和EB的风险。这些实验将产生新的知识和治疗方法，以预防接受ECMO和CPB治疗的儿童的CLS和EB，并建立新的概念，即阻断肝素+成纤维细胞生长因子-2诱导的早期毛细血管通透性变化将防止这些患者的CLS和EB，而不会使其抗凝状态正常化。